CN104945364B - A kind of A Kela determines the purposes of compound and the compound - Google Patents
A kind of A Kela determines the purposes of compound and the compound Download PDFInfo
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- CN104945364B CN104945364B CN201510419782.7A CN201510419782A CN104945364B CN 104945364 B CN104945364 B CN 104945364B CN 201510419782 A CN201510419782 A CN 201510419782A CN 104945364 B CN104945364 B CN 104945364B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention provides a kind of A Kela determines compound, the compound is the fixed hydrate of A Kela, and crystallization prepares speed soon, and crystallization processes are simple, and the yield of crystallization process can reach 95%.Therefore, be A Kela fixed further with provide wide prospect.
Description
Technical field
The present invention relates to a kind of A Kela determines the purposes of compound, the compound, belong to field of medicaments.
Background technology
A Kelading, also known as icariine, epimedium aglucone, be extract from Chinese medicine barrenwort isolated main
The new effective monomer that active component Shorthorned Epimedium P.E is obtained through enzymatic conversion, shown in its structural formula such as following formula (A)：
?《The Chinese experimental pharmacology of traditional Chinese medical formulae》2012 volume 18 14 interim disclose that " icariine is to estrogen-dependent breast
The impact of cancer MCF-7 cytosis ", and icariine and estradiol synergy are disclosed by research have and suppress E2 to lure
The proliferation function of the MCF-7 Human Breast Cancer Cells that leads.
?《Chinese comparative medicine magazine》6th phase in 2011 discloses " icariine antiangiogenic tumor cell proliferation effect in vitro
Should " article, and this article disclose effect of the icariine to tumor cell proliferation.
The preparation method of icariine is disclosed in the Chinese patent of Patent No. 200710099025.1, and the method is led to
Crossing beta-glucosidase carries out enzyme digestion reaction to icariin, carries out being recrystallized to give excessive sheep by acetone-water after enzyme digestion reaction
The sterling of leaves of pulse plants element.
The crystalline substance that a kind of A Kela determines compound is disclosed in the Chinese patent application of Application No. 201410185323.2
Type, the crystal formation are a kind of solvent-free crystal formations.
But present inventor is had found by test of many times, A Kela also exists stable in properties containing hydrate surely
Thing, therefore, be A Kela fixed further with provide wide prospect.
Content of the invention
It is an object of the present invention to provide a kind of A Kela determines compound.
It is a further object to provide the A Kela of the present invention determines compound preparing for treating cell exception
Propagation has the purposes in the medicine of related disorders.
One aspect of the present invention determines compound there is provided a kind of A Kela,
Wherein, X is 0.5 or 1.
Preferably, as X=0.5, the compound determines semihydrate for A Kela, and its crystal formation is surveyed using Cu-Ka ray
The X-ray powder diffraction for measuring is 4.9 in 2 θ0±0.20、5.90±0.20With 25.30±0.20Place's appearance.
Preferably, the crystal formation of the compound is also 9.20±0.20、9.90±0.20With 12.40±0.20Place's appearance.
Preferably, the crystal formation of the compound is also 15.40±0.20、16.60±0.20With 22.70±0.20Place's appearance.
Preferably, the crystal formation of the compound is also 18.20±0.20、18.80±0.20、20.10±0.20With 21.30±
0.20Place's appearance.
Preferably, as X=1, the compound determines monohydrate for A Kela, and its crystal formation uses Cu-Ka radionetric survey
The X-ray powder diffraction for obtaining is 5.1 in 2 θ0±0.20、6.10±0.20With 10.10±0.20Place's appearance.
Preferably, the crystal formation of the compound is also 7.80±0.20、9.40±0.20、12.60±0.20With 16.80±0.20
Place's appearance.
Preferably, the crystal formation of the compound is also 15.60±0.20、20.20±0.20、21.50±0.20With 25.50±
0.20Place's appearance.
Further aspect of the present invention additionally provides the compounds of this invention has related disorders in preparation for anti-cell abnormality proliferation
Purposes in medicine.
Preferably, the relevant disease of described abnormal cell proliferation is malignant tumour or reproducibility aplastic anemia.
Preferably, described malignant tumour include breast cancer, cervical carcinoma, oophoroma, colon cancer, carcinoma of endometrium, liver cancer,
Lung cancer, bone marrow cancer, prostate cancer or cancer of the stomach.
The beneficial effects of the present invention is：It is the fixed hydrate of A Kela that A Kela in the present invention determines compound, hydration
Compared with solvent-free crystal formation, the hydrate crystal forms of the present invention prepare speed soon to thing crystal formation, and crystallization process only needs 10 minutes.And Wu molten
Agent crystal formation crystalline rate is slow, generally requires more than 24 hours.Therefore, the production efficiency of solvent-free crystal-form compound is far below this
Bright containing crystal compound.
The hydrate crystal forms preparation process operation of the present invention is simpler, and operating process is without the need for strict temperature control.Only need
Under agitation, acetone soln fixed for A Kela is rapidly joined formation semihydrate crystal formation in water；Or water is rapidly joined Ah can
Draw in fixed acetone soln and form monohydrate crystal form.And in the preparation process of solvent-free crystal formation, need under being heated to reflux, first
First A Kela is dissolved in surely in the double solvents of acetone and water, then strictly control chilling temperature ability acquired character is preferable
Crystal formation.
Additionally, it is 90-95% that A Kela determines hydrate crystal forms in the yield of preparation process, and solvent-free crystal-form compound system
The yield of standby process is 75-85%.Under the conditions of acetone consumption identical, crystal formation is hydrated in preparation process, the body of purified water
Product consumption is 4-20 times of acetone；And solvent-free crystal formation is in preparation process, the volumetric usage of purified water is the 0.5-2 of acetone
Times.Under the conditions of 40 DEG C, as A Kela is soluble in acetone surely, water insoluble, therefore molten for water and acetone mixing
For the crystalline mother solution of liquid composition, the residual for being hydrated crystal-form compound in crystalline mother solution is less than solvent-free crystal-form compound.Therefore,
The yield of hydration crystal formation is higher than solvent-free crystal formation.
The A Kela of the present invention is determined as hydrate crystal forms determine anhydrous crystal forms with A Kela, it may have preserved well stable
Property.
Additionally, the A Kela of the present invention is hydrated the photostability that the photostability of crystal formation is better than anhydrous crystal forms surely, therefore, make
Impact of the illumination to drug storage will be reduced with the fixed aqueous crystal formation of A Kela, extend the term of validity of medicine.
Description of the drawings
Fig. 1 represents that A Kela prepared by 1 method of embodiment determines the nmr spectrum of semihydrate crystal formation.
Fig. 2 represents that A Kela prepared by 1 method of embodiment determines the nmr spectrum of anhydrous crystal forms.
Fig. 3 represents that A Kela prepared by 1 method of embodiment determines the thermogravimetric analysis of hemi-hydrate crystalline and differential scanning heat point
Analysis curve.
Fig. 4 represents the X-ray powder diffraction pattern of 1 A Kelading hemi-hydrate crystalline of embodiment.
Fig. 5 represents that A Kela of the present invention determines the thermal gravimetric analysis curve of monohydrate crystal.
Fig. 6 represents that A Kela of the present invention determines the X-ray powder diffraction pattern of monohydrate crystal.
Fig. 7 represents that A Kela determines anhydrous crystal forms through the HPLC collection of illustrative plates after illumination 5 days.
Fig. 8 represents the fixed semi-crystal type of A Kela through the HPLC collection of illustrative plates after illumination 5 days.
Fig. 9 represents the fixed hydration crystal formation in Accra through the HPLC collection of illustrative plates after illumination 5 days.
Specific embodiment
Unless otherwise indicated, term herein " A Kela determines semihydrate " refers to be determined and half by a molecule A Kela
The aquo-compound of molecular water composition.
Unless otherwise indicated, term herein " A Kela determines monohydrate " refers to be determined and one by a molecule A Kela
The aquo-compound of molecular water composition.
Unless otherwise indicated, term herein " solvent-free crystal formation " refer to A Kela determine not contain in compound water or
Other solvents, by the specific crystal formation of the special lattice vacancy arrangement form of compound molecule or atom.
Unless otherwise indicated, term herein " abnormal cell proliferation " refer to cell growth, differentiation and apoptosis inclined
From the normal growth cycle of cell.
Unless otherwise indicated, term herein " the relevant disease of anti-cell abnormality proliferation " refer to treat or prevent with
The relevant disease of abnormal cell proliferation.
Unless otherwise indicated, term herein " thermogravimetric analysis " refers to measure testing sample under programed temperature
Quality and temperature change between relation a kind of thermoanalysis technology.
Unless otherwise indicated, term herein " differential scanning calorimetry " refers to, under conditions of temperature change, survey
A kind of analytical technology that amount energy difference of the thing with respect to reference substance in the unit interval is varied with temperature.
Embodiment
Embodiment 1
It is fixed that commercially available Shorthorned Epimedium P.E enzymatic isolation method prepares A Kela
Shorthorned Epimedium P.E in the present embodiment is purchased from Shaanxi Jiahe plant Chemical Co., Ltd., and trade name is " excessive sheep
Leaves of pulse plants extract ", wherein containing the icariin that mass fraction is 90%.
Step one：It is fixed that enzymatic isolation method prepares A Kela
By commercially available 80g Shorthorned Epimedium P.E, wherein containing the icariin that mass fraction is 90%, being scattered in concentration is
In the disodium hydrogen phosphate of the pH5.2 of 1mol/L-potassium phosphate buffer 2.0L, ethanol 0.6L, RAPIDASE pectase is added
1400g, 1.4L is in 5L reactor altogether.Wherein, " pectase " is purchased from the pectin of the trade mark for RAPIDASE of DSM company
Enzyme, production code member are 984.
Reaction temperature is digested under conditions of 50 DEG C, specific condition such as table 1：
1 enzymatic hydrolysis condition of table
| Shorthorned Epimedium P.E g | Enzyme amount L | Ethanol L | Buffer solution L | Reaction temperature |
| 80 | 1.4 | 0.6 | 2.0 | 50℃ |
Detected by HPLC, reaction system is converted 70 hours, icariin is converted into A Kela to be determined, and conversion ratio reaches
90%.Due to the fixed purity of the A Kela for obtaining not enough, need to purify further.
Step 2：A Kelading half is hydrated the preparation of crystal formation
Take the Partial digestion product that step one obtains to be purified.10.0g enzymolysis product, 700mL acetone are taken in 1L beaker
In, stirring and dissolving in tepidarium.Then acetone soln fixed for A Kela is added rapidly to the burning of the purified water equipped with 4L normal temperature
In bottle, 10min is stirred vigorously, now separates out a large amount of yellow solids.Filter after solution is down to room temperature, filter cake is placed in 25 DEG C of air blast
Dry 48 hours in drying box, obtain yellow powder 9.2g, yield 92%.Sample presentation carry out nuclear magnetic resonance spectroscopy (1H NMR), obtain
Collection of illustrative plates as shown in Figure 1；Thermogravimetric analysis and differential scanning calorimetry (TGA/DSC), obtain collection of illustrative plates as shown in Figure 3；Powder spreads out
Penetrate analysis (XRPD) collection of illustrative plates as shown in Figure 4.
Comparison by Fig. 1 and Fig. 2, it can be seen that A Kela prepared by 1 method of embodiment determines semihydrate crystal formation and Fig. 2
The nmr spectrum of the solvent-free crystal formation of A Kelading goes out peak position and does not change.Additionally, at Fig. 1 displacement 2.1ppm appearance,
The peak is the hydrogen peak of acetone, as the mass content of acetone in sample is 0.2%, illustrates not containing acetone solvent in the sample.
Visible by the thermogravimetric analysis figure of Fig. 3, it is the 3.0% of example weight that sample is weightless when being heated to 80 DEG C, shows that difference is swept
Retouch thermal analysis curue and show when initial temperature is 60.3 DEG C desolventizing endothermic peak occur, exist at 253.6 DEG C and endothermic peak is melted, melt
Change enthalpy is 120.32J/g.Shown with reference to 1H NMR figure by differential scanning calorimetry and thermogravimetric analysis figure, product is a kind of hydration
Crystal formation, by calculating, the hydration crystal formation is the fixed semihydrate of A Kela.
Fig. 4 represents that A Kela determines the X-ray powder diffraction pattern of semihydrate crystal formation, can see half hydration from the figure
Thing is for about 4.9 at 2 θ angles0, about 5.90, about 9.20, about 9.90, about 12.40, about 15.40, about 16.60, about 18.20, about 18.80, about
20.10, about 20.80, about 21.30, about 22.70, about 25.30About 26.40Place's appearance.
Embodiment 2
Take the Partial digestion product that step one obtains to be purified.Take 10.0g enzymolysis product, 700mL acetone to burn in 5.0L
In bottle, stirring and dissolving in tepidarium.Then rapidly join 4L purified water under agitation, continue stirring 10min.Now separate out a large amount of
Yellow solid, filters after solution is down to room temperature.Filter cake is placed in 25 DEG C of air dry ovens and dries 48 hours, obtains yellow powder
9.5g, yield 95%.Filter cake is placed in 25 DEG C of air dry ovens and dries 48 hours.Thermogravimetric analysis (TGA), obtains as shown in Figure 5
Collection of illustrative plates；Powder diffraction analysis (XRPD) collection of illustrative plates as shown in Figure 6.
Weightless when being heated to 80 DEG C by Fig. 5 thermogravimetric analysis figure display sample is the 4.6% of sample gross weight.By meter
Calculate, the hydration crystal formation for obtaining the present embodiment determines monohydrate crystal form for A Kela.
Visible by X-ray powder diffraction, A Kela determines monohydrate crystal form about 5.10, about 6.10, about 7.80, about
9.40, about 10.10, about 12.60, about 15.60, about 16.80, about 20.20, about 21.50About 25.50Place's appearance.
Comparative example
The enzymolysis product 10g that 1 step one of embodiment is prepared is centrifuged, and removes supernatant, and precipitation uses 2L acetone solution,
Filter, then about 1L distilled water is added in filtrate, 75 DEG C of backflow dissolvings, 20 DEG C of placement crystallizations.After crystallization 24 hours, it is filtrated to get
Light yellow crystal, 60 DEG C of forced air dryings 48 hours, until the weight of crystal no longer changes, obtain A Kela fixed nothing crystal
Type.Totally 8.1 grams of anhydrous crystal forms, with respect to enzymolysis product, yield is 81%.
Embodiment 3
The evaluation of A Kelading hydration stability of crystal form
Take the fixed anhydrous crystal forms of the A Kela prepared according to comparative example method, prepare according to 1 method of embodiment
A Kela half hydration crystal formation surely, and the fixed hydration crystal formation product of the A Kela prepared according to 2 method of embodiment is each 0.2 gram
The placement of measuring cup split shed is placed in, is that 4500 ± 500 lux illumination casees are placed 5 days in illuminance, then has in detection sample
Content of material is closed, its HPLC-UV detection is respectively as shown in Fig. 7, Fig. 8 and Fig. 9.
Evaluation of result：Fig. 7 be anhydrous crystal forms through the HPLC collection of illustrative plates after illumination 5 days, wherein retention time is 7.6 minutes, protects
The impurity content that the time is 8.6 minutes and retention time is 9.3 minutes is stayed to be respectively 0.13%, 0.21% and 0.76%.Fig. 8 is
A Kelading half is hydrated crystal formation through the HPLC-UV detection after illumination 5 days, wherein retention time be 7.6 minutes, 8.6 minutes and
The impurity content of 9.3 minutes is not respectively detected, 0.05% and 0.59%.Fig. 9 is hydrated crystal formation after illumination 5 days surely for A Kela
High-efficient liquid phase color collection of illustrative plates, wherein retention time is 7.6 minutes, the impurity content of 8.8 minutes and 9.3 minutes is respectively
0.03%th, 0.04% and 0.42%.Knowable to data above, A Kela is partly hydrated the photostability of crystal formation and a hydration crystal formation surely
It is better than A Kela and determines anhydrous crystal forms.Therefore, impact of the illumination to drug storage will be reduced using the fixed aqueous crystal formation of A Kela, extends
The term of validity of medicine.
Embodiment 4
Respectively detection A Kela determine monohydrate crystal form and A Kela to determine semihydrate crystal formation thin to people's carcinoma of endometrium
Born of the same parents strain Hec1A (ATCC HTB-112TM), to liver cancer Huh-7 cell line (purchased from Japanese Cancer Research
Bank (JCRB), Tokyo, Japan), to acute myeloid leukemia cells in children MV-4-11 (ATCC CRL-9591TM), human breast carcinoma
Cell line MDA-MB-231 (ATCC HTB-26TM), stomach cancer cell line MGC-803 (the true Industrial Co., Ltd. in Shanghai), lung cancer thin
Born of the same parents strain H460 (ATCC HTB177TM), colon cancer cell line LS 174T (ATCC CL-188TM), pancreas cancer cell strain PANC-1
(ATCC CRL1469TM), ptostate cancer PC 3 cell line (ATCC CRL1435TM), cervical cancer cell lines Hela (ATCC
CCL2TM), Ovarian Cancer Cells SKOV3 (ATCC HTB-77TM) and myeloma cell strain RPMI8226 (the true industry in Shanghai
Co., Ltd) inhibitory action.Detection method is identical with the detection method disclosed in 201410185323.2 patent applications.
Determine nothing compared with hydrate crystal forms with the A Kela of 201410185323.2 patent application publication, testing result shows do not have
Have either A Kela to determine monohydrate crystal form or A Kela determine semihydrate crystal formation to the inhibiting rate of tumour cell all and Ah
Can draw and determine identical nothing hydrate crystal forms, without any difference, therefore not interfere with A Kela fixed to tumour cell for the visible crystallization water
Inhibitory action.
Claims (5)
1. a kind of A Kela as shown in following formula (I) determines the semihydrate crystal formation of compound,
Characterized in that, when X is 0.5, the X-ray powder diffraction that its crystal formation is obtained using Cu-Ka radionetric survey is 4.9 ° in 2 θ
±0.2°、5.9°±0.2°、25.3°±0.2°、9.2°±0.2°、9.9°±0.2°、12.4°±0.2°、15.4°±0.2°、
Go out at 16.6 ° ± 0.2 °, 22.7 ° ± 0.2 °, 18.2 ° ± 0.2 °, 18.8 ° ± 0.2 °, 20.1 ° ± 0.2 ° and 21.3 ° ± 0.2 °
Peak.
2. a kind of A Kela as shown in following formula (I) determines the monohydrate crystal form of compound, it is characterised in that
As X=1, the X-ray powder diffraction that its crystal formation is obtained using Cu-Ka radionetric survey is 5.1 ° ± 0.2 °, 6.1 ° in 2 θ
±0.2°、10.1°±0.2°、7.8°±0.2°、9.4°±0.2°、12.6°±0.2°、16.8°±0.2°、15.6°±0.2°、
Appearance at 20.2 ° ± 0.2 °, 21.5 ° ± 0.2 ° and 25.5 ° ± 0.2 °.
3. the crystal formation described in claim 1 or 2 is preparing the purposes having in the medicine of related disorders for anti-cell abnormality proliferation.
4. purposes according to claim 3, it is characterised in that the relevant disease of described abnormal cell proliferation is pernicious swollen
Knurl or reproducibility aplastic anemia.
5. purposes according to claim 4, it is characterised in that described malignant tumour includes breast cancer, cervical carcinoma, ovary
Cancer, colon cancer, carcinoma of endometrium, liver cancer, lung cancer, bone marrow cancer, prostate cancer or cancer of the stomach.
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| CN201510419782.7A CN104945364B (en) | 2014-09-16 | 2015-07-16 | A kind of A Kela determines the purposes of compound and the compound |
| TW104130599A TWI632907B (en) | 2014-09-16 | 2015-09-16 | Icaritin compound crystal form and application thereof |
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| CN201410472018.1A CN104230870A (en) | 2014-09-16 | 2014-09-16 | Icaritin compound and application thereof |
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| CN201510419782.7A CN104945364B (en) | 2014-09-16 | 2015-07-16 | A kind of A Kela determines the purposes of compound and the compound |
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| CN110699263B (en) * | 2019-10-29 | 2021-05-11 | 浙江工业大学 | Aspergillus niger YH-6 and application thereof in improving content of icaritin in epimedium |
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| CN101302548B (en) * | 2007-05-09 | 2011-04-13 | 北京珅奥基医药科技有限公司 | Preparation of icaritin |
| CN101200743B (en) * | 2007-12-17 | 2010-12-15 | 北京珅奥基医药科技有限公司 | Method for preparing hydrated icaritin |
| CN102038673B (en) * | 2009-10-20 | 2012-07-25 | 北京珅奥基医药科技有限公司 | Application of hydroxyl benzopyrone compound for preparing medicament for treating leukemia |
| CN103936705B (en) * | 2014-05-05 | 2015-10-21 | 北京盛诺基医药科技有限公司 | The crystal formation of A Kelading compound, the medicine containing this crystal formation and purposes |
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